Many clinical situations in musculoskeletal care require a bone reconstruction strategy. Novel orthopaedic biomaterials that effect guided bone growth into biodegradable polymeric composite scaffolds are candidates to address such requirements, and the goal that has motivated the development of these materials is the eventual elimination of autograft bone harvest for transplantation into skeletal regeneration sites. For the past decade, our laboratory has done extensive work on the synthesis and characterization of in situ polymerizable materials, in vitro evaluation of cell-biomaterial interactions, and in vivo assessment of scaffold function in small animal models. This proposal focuses on the translation of our bone tissue engineering work toward initial human use via three integrated aims. In Aim 1, we will encapsulate vascular endothelial growth factor (VEGF) and bone morphogenetic protein-2 (BMP-2) into two hydrogel porogens that have different degradation rates, designed to generate two sequential pore systems in the self-crosslinking poly(propylene fumarate)-co- poly(caprolactone) (PPF-co-PCL) composite biomaterial scaffold. This dual porosity generation will affect dual, sequential delivery of angiogenic and osteoinductive factors to provide an initial vascular network that will support the subsequent osteogenic process. In Aim 2, we will determine the in vivo effect of PPF-co-PCL composite scaffolds on bone formation in a rabbit posterolateral spine fusion model. We will evaluate both injectable and preformed scaffold strategies in this model. The injectable strategy involves injection of a polymerizing scaffold formulation into a bony defect to form a composite biomaterial. The preformed strategy utilizes solid freeform fabrication to manufacture a composite biomaterial implant that has a specified size, shape, and internal microarchitecture. The design goal for this composite biomaterial implant is to fabricate a three-dimensional scaffold that directs the bone regeneration process and provides mechanical support to the reconstructed region during polymer degradation and new bone formation. In Aim 3, we will assess the bone regeneration performance of PPF-co-PCL composite scaffolds in a large animal model of a clinically relevant human surgical procedure as a translational step toward initial human use. We have selected an anterior- posterior sheep spine reconstruction, consisting of both a posterolateral intertransverse process fusion and an anterior skeletal gap (discectomy/vertebrectomy) reconstruction, utilizing our injectable and preformed scaffold strategies to accomplish this goal.